SUMMARY Staphylococcus aureus is a major human pathogen of the respiratory tract and influenza co-infection is a major predisposing factor for subsequent infection. Colonization of the upper respiratory tract is also a significant factor in infection, with aspirated organisms reaching the lung and leading to host immunopathology. The host processes involved in S. aureus colonization and subsequent dissemination to the lung are not well understood, but we have identified two pathways that are activated upon S. aureus infection, the type I and type III IFN pathways. Type I and III IFN signaling contribute to the ability of S. aureus to colonize the nasopharynx during influenza co-infection as well as during acute pneumonia where they contribute to excessive immunopathology. In Aim 1 we will investigate mechanisms behind IFNs increasing susceptibility to S. aureus colonization during influenza co-infection. This aim will utilize an in vivo co-infection model of colonization examining: IFNs changing the cytokine response, antimicrobial peptide changes of the microbiome and the role of sialic acid and influenza neuraminidase in biofilm formation and colonization. In Aim 2 we will examine the consequences of respiratory epithelial IFN activation to S. aureus, examining changes in cytokines and their influence of macrophages and neutrophil function. We will also examine the utility of IFN antibody neutralization in clearing infection and in concert with current antimicrobials. At the conclusion of these studies, we will have expanded our knowledge on how IFNs contribute to the pathogenesis of S. aureus colonization and pneumonia, and will have identified targetable mechanisms for therapeutic amelioration of host immunopathology due to IFN production.